Pain is considered to be a critical national health problem that costs this country over $100 billion each year in health costs and lost productivity (NIH, 2006). In addition, it has been reported that women are over-represented for a number of chronic pain conditions (e.g., temporomandibular disorders, arthritis, fibromyalgia) compared to men. The mechanisms responsible for these sex differences, however, have yet to be fully determined, thus, the overall objective of the proposed research is to examine whether men and women differ in selected mechanisms of endogenous pain modulation. One form of endogenous pain modulation is exercise-induced analgesia (EIA). Numerous studies have indicated an attenuation of pain following exercise, and therapeutic exercise programs are an important element in the treatment of many chronic pain syndromes. Thus, it is surprising how little is known regarding this form of endogenous pain modulation in men and women. Currently, the mechanisms responsible for EIA are poorly understood but results from the animal research indicate that multiple analgesic systems exist, and there are sex differences in the underlying neurochemical mediation of analgesia. The primary purpose of the proposed research is to examine opioid and endocannabinoid mechanisms of EIA in men and women. A double-blind placebo- controlled crossover design employing an opioid blockade methodology will be utilized in the proposed research. A total of 60 men and women between the ages of 18-40 yrs will be recruited to participate in a familiarization session and two randomly assigned experimental sessions. Participants will undergo pain testing (i.e., noxious thermal and pressure stimuli) before and after exercise following double-blind administration of an opioid antagonist and a placebo. Blood will be drawn before and following exercise to examine endocannabinoid responses to exercise. Understanding why men and women differ in pain sensitivity has important implications for furthering our knowledge of the etiology, mechanisms and treatment of pain PUBLIC HEALTH RELEVANCE: The perception of pain is modulated by multiple endogenous analgesic systems, and there is evidence that these systems operate differently in men and women. Given the substantially greater prevalence of many clinical pain conditions in women vs men, it is essential to gain a better understanding of sex differences in endogenous pain inhibitory mechanisms which will ultimately permit the tailoring of better treatments to enhance pain control in both men and women.